This Program Project constitutes three individual Research Projects, one Research Support Core and an Administrative Core, under the direction of Principal Investigator, John P. Moore, Ph.D. and co-investigator, Mark Wainberg, M.D.. The purpose of this program is to conduct in vitro and in vivo pre- clinical and animal model-based research intended to identify and characterize inhibitors of HIV-1 replication that might be suitable for commercial development as topical microbicides. The applicant?s central hypothesis is that specific inhibitors of HIV-1 attachment, fusion and entry could prevent or hinder the vaginal or rectal transmission of HIV-1, when properly formulated and applied to women or men prior to sexual intercourse. The applicant believes that microbicides should be designed and developed based on rational scientific principles, taking into account accumulated knowledge of the stages of the viral life cycle to be impeded, the mechanism of action of the candidate inhibitors, and the biological processes involved in HIV-1 transmission. The applicant does not intend to study microbicide candidates that have a non-specific mechanism of action, that have a broad-spectrum activity against multiple pathogens, or that are also spermicides. His goal is to use his collective knowledge of HIV-1 virology and mammalian biology to help develop a mechanism- based, HIV-l-specific microbicide(s). Towards this goal, the applicant has obtained and will comparatively evaluate in vitro and in vivo, both alone and in combination, several different inhibitors of defined stages in HIV-1 entry. Rather than focus on a single compound, the applicant seeks to identify the best inhibitor(s) to move into clinical development. He proposes: Research Project I: Robin Shattock, Ph.D., Characterization of HIV-1 fusion/entry inhibitors in human cervical and rectal tissue models; Research Project II: Melissa Pope, Ph.D., Assessment of fusion/entry inhibitors in DC-T cell mixtures; Research Project III: Ronald Veazey, Ph.D., Evaluation of fusion inhibitors for protection from SHIV and SIV vaginal or rectal challenge in macaques; Scientific Core: John P. Moore, Ph.D., Fusion-Inhibitor Acquisition, Evaluation and Formulation; Administrative Core: John P. Moore, Ph.D.